Type 2 diabetes (T2DM) has become a major public health issue (˜26 million Americans have diabetes and ˜79 million more have pre-diabetes) and the epidemic continues to grow such that diabetes may affect 1 in 3 Americans by 2050. While a number of therapies are available, they can significantly impact life quality, i.e., multiple daily insulin injections and often are not able to prevent devastating complications. T2DM is characterized by peripheral insulin resistance and loss of functional beta cell mass. When pancreatic beta cells can no longer keep up with the increased insulin requirements they decompensate leading to progressive beta cell dysfunction, impaired insulin gene transcription (1,2), irreversible beta cell loss by apoptosis (3,4) and hyperglycemia resulting in a vicious cycle with worsening of the diabetes. Promoting functional beta cell mass would therefore be an attractive therapeutic approach, be it by enhancing beta cell survival or beta cell function, i.e., insulin production. This approach would enhance the patient's own natural insulin production and reduce or eliminate the need for daily insulin injections and improve outcome.
microRNAs (small, 20-24 nucleotide, non-coding RNAs) recognize and bind to target mRNAs through imperfect base pairing leading to destabilization or translational inhibition of the target mRNA and thereby downregulate target gene expression (20,21). However, their overall role in beta cell biology is still not clear (24).
The present invention overcomes previous shortcomings in the art by providing methods and compositions for modulating the activity of miR-204, e.g., to treat disorders associated with abnormal or altered insulin production.